Dataset Information

Multi-omic Landscape of Airway Microbe-Host Interactions in Chronic Obstructive Pulmonary Disease

ABSTRACT:

The mechanistic role of the airway microbiome in chronic obstructive pulmonary disease (COPD) remains largely unexplored. We present a landscape of airway microbe-host interactions in COPD by an in-depth profiling of sputum metagenome, metabolome, host transcriptome and proteome from 99 COPD patients and 36 healthy individuals. Multi-omic data were integrated using a sequential mediation analysis, to assess in silico associations of the microbiome with neutrophilic or eosinophilic inflammation, two primary COPD inflammatory endotypes, mediated through microbial metabolic interaction with host gene expression. Mechanistic links of microbiome-metabolite-host interaction were identified leveraging microbial genetic information and established metabolite-human gene pairs. The strongest link for neutrophil-predominant COPD was altered tryptophan metabolism driven by airway lactobacilli resulting in reduced indole-3-acetic acid (IAA), which was in turn linked to perturbed host IL-22 signaling and epithelial cell apoptosis pathways. In vivo and in vitro studies showed that airway microbiome-derived IAA mitigates neutrophilic inflammation, apoptosis, emphysema, and lung function decline, via IL-22-mediated macrophage-epithelial cell crosstalk. Intranasal inoculation of two airway lactobacilli restored IAA and recapitulated its protective effects in mice. These findings provide the rationale for therapeutically targeting microbe-host interaction in COPD.

Linked studies:

UPLC-MS/MS assays of original cohort human samples are reported in this study.

UPLC-MS/MS assays of more recent cohort human samples are reported in MTBLS5423.

UPLC-MS/MS assays of more recent murine samples are reported in MTBLS6894.

INSTRUMENT(S): Liquid Chromatography MS – negative - reverse phase, Liquid Chromatography MS - positive - reverse phase

SUBMITTER: Zhang Wang

PROVIDER: MTBLS4017 | MetaboLights | 2022-06-20

REPOSITORIES: MetaboLights

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			Action	DRS
	MTBLS4017	Other
	FILES	Other
	a_MTBLS4017_LC-MS_NEG_hilic_metabolite_profiling.txt	Txt
	a_MTBLS4017_LC-MS_POS_hilic_metabolite_profiling.txt	Txt
	files-all.json	Other

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Project description:Progressive decline in lung function is a hallmark of chronic obstructive pulmonary disease (COPD). Although airway dysbiosis occurs in COPD, whether it contributes to disease progression remains unknown. Here, through a longitudinal analysis on 181 COPD individuals from two large cohorts involving four UK clinical centers, we showed that baseline airway dysbiosis, characterized by enrichment of opportunistic pathogenic taxa, was associated with rapid forced expiratory volume in one second (FEV1) decline over two years. Co-presence of Moraxella, Staphylococcus and Stenotrophomonas was associated with an accelerated FEV1 decline by 139.7 mL/year. The dysbiosis was associated with exacerbation-related FEV1 fall and sudden FEV1 fall at clinical stability, two critical events contributing to long-term FEV1 decline. The microbiota association with FEV1 decline was validated in a third, independent cohort in China. Human multi-omics, murine and cellular mechanistic studies showed that chronic airway colonization of Staphylococcus aureus promoted lung function decline through producing homocysteine, which elicited an apoptosis-to-NETosis shift in neutrophils toward persistent inflammation via AKT1-S100A8/A9 axis. Prophylactic and therapeutic depletion of S. aureus via bacteriophage restored lung function in emphysema mice. These results provide a fresh approach to slow COPD progression by targeting the airway microbiome. Linked studies:UPLC-MS/MS assays of human samples are reported in this study.UPLC-MS/MS assays of murine samples are reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS6894' rel='noopener noreferrer' target='_blank'>MTBLS6894</a>.UPLC-MS/MS assays of original cohort human samples are reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS4017' rel='noopener noreferrer' target='_blank'>MTBLS4017</a>.

Project description:The toll-like receptors (TLRs) are important components of the respiratory epithelium host innate defense, enabling the airway surface to recognize and respond to a variety of insults in inhaled air. Based on the knowledge that smokers are more susceptible to pulmonary infection and the airway epithelium of smokers with chronic obstructive pulmonary disease (COPD) is characterized by bacterial colonization and acute exacerbation of airway infections, we assessed whether smoking alters the expression of TLRs in human small airway epithelium, the primary site of smoking-induced disease. Microarrays were used to survey the TLR family gene expression in small airway (10th-12th order) epithelium from healthy nonsmokers (n=60), healthy smokers (n=73) and smokers with COPD (n=36). Using the criteria of detection call of present in ≥50%, 6 of 10 TLRs (1, 2, 3, 4, 5 and 8) were expressed. Compared to nonsmokers, the most strikingly changed gene is TLR5, which down-regulated in healthy smokers (1.4-fold decrease, p<10-13) and in smokers with COPD (1.6-fold, p<10-14). TaqMan RT-PCR confirmed these observations. Bronchial biopsies immunofluorescence showed that TLR5 protein was expressed mainly on the apical side of the human airway epithelium and decreased in healthy smokers and smokers with COPD. In vitro studies showed that the level of TLR5 downstream genes, IL-6 and IL-8 were highly induced in TLR5 high-expressing cells compared to TLR5 low-expressing cells after flagellin exposure. In the context that TLR5 functions to recognize pathogens and activate innate immune responses, the smoking-induced down-regulation of TLR5 likely contributes to smoking-related susceptibility to airway infection. The toll-like receptors (TLRs) are important components of the respiratory epithelium host innate defense. Microarrays were used to survey the TLR family gene expression in small airway (10th-12th order) epithelium from healthy nonsmokers (n=60), healthy smokers (n=73) and smokers with COPD (n=36). Using the criteria of detection call of present in ≥50%, 6 of 10 TLRs (1, 2, 3, 4, 5 and 8) were expressed. Compared to nonsmokers, the most strikingly changed gene is TLR5, which down-regulated in healthy smokers (1.4-fold decrease, p<10-13) and in smokers with COPD (1.6-fold, p<10-14). In the context that TLR5 functions to recognize pathogens and activate innate immune responses, the smoking-induced down-regulation of TLR5 likely contributes to smoking-related susceptibility to airway infection. *** Processed data not provided for all gene expression records. ***

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Multi-omic Landscape of Airway Microbe-Host Interactions in Chronic Obstructive Pulmonary Disease

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